IMMUNE RECONSTITUTION AND HIV

Jason Gillman, MD AIDS Arms, Inc. November 15, 2016

Disclosures

Bristol-Myers Squibb

◦ Advisory board

Gilead Sciences

◦ Speakers bureau

Abbvie

◦ Speakers bureau

Overview

Definition and Pathogenesis

Risk factors

Timing and Incidence

IRIS syndromes and their management ◦ MAC

◦ TB

◦ PML

◦ CMV

◦ Cryptococcus

◦ KS

Prevention ◦ Timing of HAART initiation

What’s New

No major guideline updates in the last 6

months

Case 1

51yo Ethiopian female, immigrated to the U.S. in August, 2013, admitted in October with cough, dyspnea, and weight loss, found to have a new diagnosis of HIV (CD4 21, VL 2 million c/mL) as well as pulmonary TB (culture-confirmed). HIV genotype was wild-type, and she was treatment naïve.

She was started on RIPE, and ~two weeks later on Atripla. Discharged in stable condition

She returned to the hospital 8 days later with fever to 38.6C, tachycardia, hypoxia, and worsening pleuritic chest pain and cough

CT chest showed increased cavitation of mediastinal lymph nodes and larger bilateral pleural effusions

HIV RNA had declined to 6684 c/mL, although she had to self-discontinue Atripla due to nausea. CD4 count unchanged.

IRIS/IRD

Immune Reconstitution Inflammatory Syndrome (IRIS)

◦ Also referred to as immune reconstitution disease (IRD)

“Paradoxical” IRIS - Worsening of a recognized OI

“Unmasking” IRIS – Symptoms from an unrecognized

pre-existing OI that manifest in the setting of improving

immunologic function.

Example: TB-IRIS

Patient on treatment for

TB

(Worsening disease)

Paradoxical IRIS

ART

Patient not known to have

TB

(Symptoms of TB)

Unmasking IRIS

ART

Pathogenesis

IRIS

Suppresion of viremia

Immune Recovery

Antigenic Burden

Genetic susceptibility

Cytokines

Tmem

Tnaive

Treg

Mayer K H , and French M A Clin Infect Dis. 2009;48:101-107

Incidence Study Type Incidence

Michelet, et al. AIDS. 1998 Retrospective 68%

French, et al. HIV Med. 2000 Retrospective 25%

Ratnam, et al. CID. 2006 Retrospective 23%

Murdoch, et al. AIDS. 2008 Prospective 10%

Grant, et al. PLoS One. 2010 Prospective 7.6%

Muller, et al. Lancet Infect Dis. 2010 Meta-analysis 13%

Previously diagnosed OI Incidence of IRIS

Kaposi’s Sarcoma 6.4%

Herpes Zoster 12.2%

TB 15.7%

PML 16.7%

Cryptococcal meningitis 19.5%

CMV retinitis 37.7%

Risk Factors:

CD4 count < 100

Disseminated infection (high antigenic

burden)

Shorter interval between initiating

treatment for OI and starting HAART

Younger age

Rapidity and magnitude of virological

response to ART

Fungal infection (other than PJP)

Timing:

Highly variable

As little as 3 days after initiation of HAART, up to 3 months or longer

IRD can occur early due to the immediate improvement in immune function that occurs with virologic suppression

For the ID board exams – remember 2-4 weeks

Diagnosis:

No strict diagnostic criteria, diagnosis

based on degree of clinical suspicion

Case Definition (INSHI)

1. Response to anti-retroviral therapy by: ◦ a. receiving HIV anti-retroviral therapy and;

◦ b. virologic response with >1 log10 copies/mL decrease in HIV RNA (if available).

2. Clinical deterioration of an infectious or inflammatory condition temporally related to ART initiation.

3. Symptoms cannot be explained by: ◦ a. expected clinical course of a previously recognized

and successfully treated infection

◦ b. medication side effect or toxicity

◦ c. treatment failure

◦ d. complete non-adherence.

Challenges:

Diagnosis is clinically challenging, one must

differentiate from:

◦ Progression of the initial OI

antimicrobial resistance

treatment failure for any reason, including poor

adherence

◦ Development of a new OI

◦ Unrelated organ dysfunction

◦ Drug toxicity

Allergic Reaction – Abacavir Hypersensitivity

IRIS SYNDROMES

Clinical Manifestations:

Symptoms are diverse and have not been

defined precisely

Usually characterized by:

◦ Fever

◦ Worsening of the clinical manifestations of

underlying OI.

Causes of IRIS: Mycobacteria

◦ MAC

◦ TB

Viruses

◦ PML

◦ CMV

◦ Herpes virus VZV

HSV

◦ HBV/HCV

Fungal

◦ Cryptococcus

◦ Histoplasmosis

◦ PJP

KS

Toxoplasmosis

Parvovirus B19

Strongyloides stercoralis and

other parasites

Sinusitis

Folliculitis

Rheum/autoimmune

RA, SLE

Graves disease

Sarcoid

Tattoo ink

AIDS-related lymphoma

Guillain-Barre Syndrome

Case 2

50 y/o man with HIV, CD4 initially 16, VL 2 million, PPD neg

Started on HAART

Returned to clinic with tender lump in axilla one month later

◦ 1 x 2 cm, firm mass, almost cystic

◦ No overlying cellulitis

◦ CD4 up to 192, VL down to 4K

Referred to FNA clinic, around which time it had started to drain

Sample was sent for culture, AFB stain negative

2 months later culture found to be growing MAC.

MAC-IRIS Incidence ~ 3.5% among patients with CD4 < 100

Median time to onset of *symptoms is 3 weeks after ART initiation

Usually unmasking of subclinical disease (75% of cases)

Peripheral lymphadenitis

• Enlarged lymph node

• Draining sinus

• Less than half with fever

Pulmonary thoracic disease

• Fever

• Night sweats

• Cough

• Dyspnea

• CT findings

• Mediastinal lymphadenopathy

• Parenchymal infiltrates

• Cavitary lesions

• Nodules

Intra-abdominal disease

• Fever

• Night sweats

• Abdominal pain

• CT findings

• Intra-abdominal lymphadenopathy

Phillips P, et al. CID. 2005

Riddell J, et al. J Translational Med. 2007

MAC-IRIS: Management

Anti-mycobacterial therapy

◦ Azithromycin + ethambutol (+/- rifabutin)

For moderate-severe IRIS

◦ Initial treatment with NSAIDs (CIII)

◦ If no improvement, prednisone 20-40 mg daily

for 4-8 weeks (CII)

Relapse is common after stopping

steroids

Symptoms may persist up to 6 months

TB, HIV, and IRIS

HIV and TB co-infection

◦ Pulmonary disease

◦ Lymphadenitis

◦ Intracranial tuberculomas/meningitis

◦ Cutaneous lesions

◦ Peritonitis

◦ Epididymitis/Prostatitis

◦ Cystitis

◦ Granulomatous nephritis/hepatitis

◦ Osteomyelitis

TB-IRIS Can occur with treatment of TB in the

absence of ART

◦ Release of new antigen targets during mycobacterial killing

◦ Restoration of TB-induced immunosuppression

Incidence for patients started on ART is ~ 15%. Time to onset is typically 2-4 weeks

◦ Resolution of symptoms in ~ 3 months

◦ Generally paradoxical IRIS (except in developing countries where the diagnosis may be missed)

Meintjes, et al. Clin Chest Med. 2009

Worsening radiographic

infiltrate

(50% of patients starting ART)

Enlarging serous effusions

Enlarging lymph node

Fever

A) Time of diagnosis of TB

B) 3 weeks after ART initiation

Meintjes, et al. Clin Chest Med. 2009

TB-IRIS: Management

Continue HAART and continue RIPE

Prednisone 1.5 mg/kg/day x 2 weeks,

followed by 0.75 mg/kg/day x 2 weeks

◦ This steroid regimen was evaluated in a

randomized, double-blind placebo-controlled

trial

◦ Decreases hospital days (p=0.04), and

improves both symptoms and chest

radiographs at 2 and 4 weeks

Meintjes, et al. AIDS. 2010

TB-IRIS: Management

For some patients, 4 weeks is insufficient,

and DHHS guidelines suggest that

tapering steroids over 3 months may be

considered (BIII)

NSAIDs may be considered for mild TB-

IRIS (CIII)

Needle aspiration of effusions for

symptomatic relief

Reminder: Steroids Up Front

Patients with TB of the CNS or pericardium should receive adjunctive steroids at the time RIPE is initiated (A1)

1. Thwaites GE, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004 Oct

21;351(17):1741-51.

2. Hakim JG, et al. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive

tuberculous pericarditis in HIV seropositive patients. Heart. 2000 Aug;84(2):183-8.

CNS TB1

• Dexamethasone 0.4 mg/kg/day x 4 weeks

• Taper 0.1 mg/kg/day per week x 4 weeks

• Taper 1 mg/day per week x 4 weeks

Pericardial TB2

• Prednisone 60 mg daily, tapered by 10 mg every week x 6 weeks

Case 3 40 y/o man with HIV p/w word

finding difficulty R hemiparesis and

seizure. CD4 48.

LP + JC Virus on PCR

Started on HAART

2.5 months later presented with

worsening aphasia and had repeat

MRI. CD4 225, VL undetectable.

HAART held x 2 wks, pt treated with

dexamethasone.

2.5 yrs later, only mild residual word-

finding deficit.

Case and images from Tan and Koralnik. Lancet Neurol. 2010

PML-IRIS HIV+ patients co-infected

with JC virus with CD4 < 200 may develop Progressive multifocal leukoencephalopathy (PML)

10 – 20% of pts develop new or worsening neurologic symptoms following initiation of HAART.

Tan et al. Neurology. 2009

Classic PML

PML-IRIS

FLAIR sequence T1 post-Gadolinium

Tan and Koralnik. Lancet Neurol. 2010

PML-IRIS

Mediated by an influx of CD8+ T-cells into

existing lesions

◦ JCV actually less likely to be detected in CSF

IRIS with PML doesn’t seem to alter survival

(1 yr survival rate 54% vs 49% in PML-IRIS

vs PML without IRIS).

Marzocchetti, et al. Neurology. 2009

PML-IRIS: Management

There are no effective anti-viral drugs for JCV ◦ Continue HAART (AIII)

Steroids are controversial, but recommended for patients with contrast-enhancing lesions on MRI (BIII). ◦ Methylprednisolone 1 gm IV daily x 3 days

◦ Prednisone 60 mg PO daily, tapered over 6 weeks

Greatest benefit of steroids is seen when: ◦ Started early after recognition of IRIS

◦ Tapered over a prolonged course (6-12 weeks)

Tan, et al. Neurology. 2009

CMV and IRIS Immune reconstitution disease occurs in patients with

inactive CMV retinitis who begin ART

◦ Immune recovery uveitis (IRU) Anterior uveitis

Vitritis

Cystoid macular edema

Epiretinal membranes

Retinal neovascularization

The most common OI to result in immune reconstitution disease following ART initiation (~38% incidence)

Symptoms:

◦ Anterior chamber: ocular pain and photophobia

◦ Posterior chamber: painless floaters and decreased visual acuity

Risk Factors for IRU

CMV involving >30% retinal surface area

at the highest risk

Treatment of CMV retinitis with cidofovir

compared to an alternative regimen

Almost exclusively occurs in patients with

immune recovery to CD4 > 100

◦ Does not occur in patients with a virologic

response but no immune recovery

Goldberg, et al. Retina. 2005

Goldberg, et al. Retina. 2005

Management of IRU/IRV

Corticosteroids and

anti-CMV therapy (CIII)

Anterior chamber:

topical corticosteroids

Posterior chamber:

periocular or

intravitreal

corticosteroid

injections

Kosobucki, et al. Am J Ophthalmol. 2004

IRIS and Cryptococcus:

~20% of patients with cryptococcal meningitis and HIV develop IRIS after initiation of ART.

Presentation ◦ Meningeal (73.7%)

◦ Other CNS complications (11%)

◦ Lymphadenopathy (11%)

◦ Pneumonitis (4.5%)

Timing: delayed compared to TB (1-10 months)

The key CSF findings are elevated opening pressure and elevated CSF WBC, with sterile cultures

Haddow LJ, et al. Lancet Infect Dis. 2010

Risk factors for C-IRIS

Fungal burden (initial CrAg titer)

Lack of initial CSF inflammation (CSF

WBC < 25 cells/µL and protein < 50

mg/dL)

Early HAART initiation*

Baseline HIV viral load and baseline CD4

do not appear to be risk factors

Sungkanuparph S, et al. CID. 2009

Bicanic T, et al. JAIDS. 2009

Boulware DR, et al. JID. 2010

C-IRIS: Management

Continue ART

Continue anti-fungal therapy ◦ Re-induction with amphotericin B is unnecessary

if CSF cultures are negative

Reduce ICP with serial LP (AII)

For severe symptoms, a brief course of corticosteroids may be considered (CIII)

IRIS has been shown to increase mortality from cryptococcal meningitis, mainly in Africa

Kaposi’s Sarcoma and IRIS

High-risk of IRIS with KS

◦ Characterized by enlarging lesions and worsening peripheral edema

Visceral KS-IRIS can have mortality up to 50%

Visceral KS

Mucocutaneous KS

TB

PJP

Achenbach CJ, et al. CID. 2012

KS-IRIS: Management

Continue HAART (AIII)

Do not give steroids

◦ Causes growth of the tumor

Chemotherapy is indicated for visceral KS (AI)

and can be considered for severe cutaneous KS

(BIII)

TIMING OF ART

INITIATION

Preventing IRIS

The strongest risk factor for developing

IRIS is a baseline CD4 < 100

The optimal time to initiate ART is before

the patient develops advanced AIDS

Initiation of ART in the setting of Acute OI:

Advantages

For some OI’s, initiation of ART is the only effective treatment ◦ Cryptosporidiosis

◦ Microsporidiosis

◦ Progressive multifocal leukoencephalopathy (PML)

◦ KS

Starting ART as secondary prevention: a second OI is less likely to occur if ART is started promptly rather than delaying initiation.

ART malabsorption subtherapeutic serum levels antiretroviral drug resistance

ART toxicities vs. disease manifestations vs. OI drug toxicities

Drug-drug interactions between ART and other antimicrobials

Renal or hepatic dysfunction from acute OIs complicated ART dosing

IRIS

Initiation of ART in the setting of Acute OI:

Disadvantages

When to Start ART during Acute OI

Late Early

ACTG A5164

RCT of “early” ART (within 14 days of OI treatment) vs “late” (after completion of OI treatment) (N=282)

Primary endpoint : AIDS progression or death at 48 weeks ◦ OI distribution

PJP 63%

Crypto meningitis 12%

Serious bacterial infection12%

Zolopa 2009

In a sub-study published the following year, early ART did not

increase the risk of IRIS

What about TB and cryptococcal

meningitis?

TB: Five Randomized Controlled Trials

SAPiT ACTG 5221 CAMELIA OXTREC

023-04

TB-HAART

TB status Known Known/suspected Known TB meningitis Known

Mean Age 34 34 35 28.5 32

N 429 809 661 253 1675

CD4 cutoff <500 <250 < 200 < 200 > 220

Median CD4 150 77 25 41 367

Median VL 5.21 log10 5.43 log10 5.64 log10 5.4 log10 Not reported

Early ART Within 4 weeks Within 2 weeks Within 2

weeks

Within 7 days After 2 weeks

Late ART Within 8 weeks 8-12 weeks Within 8

weeks

After 8 weeks After 6 months

ART regimen DDI, 3TC, EFV TDF, FTC, EFV d4T, 3TC, EFV AZT, 3TC, EFV AZT, 3TC, EFV

Setting South Africa Africa, Asia, N/S

America

Cambodia Vietnam South Africa,

Tanzania, Uganda,

Zambia

Median follow up

(months) 17.7 25 25 12 24

TB: Conclusions

Overall mortality

benefit for early

ART?

Mortality benefit for

patients with CD4 < 50

Rates of IRIS increased for

early ART?

SAPiT No Yes Yes (16% vs 7%)

ACTG

5221

No Yes Yes (11% vs 5%)

CAMELIA Yes (but median

CD4 25)

Yes Yes (HR 2.5)

OXTREC No No More grade 4 adverse

events (p=0.04)

TB-HAART No N/A (CD4 > 220 in all) No (10% vs 10%)

1. ART is recommended for all HIV-infected patients with TB (AI)

2. ART should be started within 2 weeks of TB treatment for patients

with a CD4 count < 50 (AI)

3. For all others ART may be delayed 8-12 weeks (AI)

4. ART should be delayed in patients with TB meningitis

Extremely Early ART with TB?

TB-HAART (CD4 < 200)

◦ Randomized to start ART at week 1, 4, or 8

◦ No survival benefit to starting ART 1 week

after TB therapy

◦ Among patients who died during the trial:

higher rate of TB treatment interruption due

to hepatotoxicity in the week 1 group

Crypto: Timing of ART

Zimbabwe study (Makadzange, et al, 2010)

• Early initiation of ART (within 72 hours) versus delayed (>10 weeks) resulted in higher mortality (HR 2.85)

• Cryptococcal meningitis was treated with fluconazole 800 mg daily

Botswana study (Bisson, et al, 2013)

• Early ART (within 7 days) versus delayed (> 28 days) did not improve the rate of fungal clearance from CSF

• Early ART resulted in a higher rate of IRIS (54% versus 0%)

• Cryptococcal meningitis was treated with amphotericin B 0.7 mg/kg x 14 days

COAT study (Boulware, et al, 2014)

• Terminated early by the DSMB

• The patients randomized to early ART (1-2 weeks) versus delayed ART (5 weeks) had substantially higher mortality at 26 weeks (45% versus 30%, p=0.03)

• Cryptococcal meningitis was treated with amphotericin B 0.7 mg/kg + fluconazole 800 mg daily x 14 days

When to Start ART During Acute OIs

Early Treatment (< 2 wks):

Pneumocystis pneumonia

Toxoplasma gondii encephalitis

Mycobacterium avium complex disease

CMV disease

Esophageal candidiasis

Bacterial

TB (CD4 < 50 cells/μL)

Delay Treatment:

• TB (CD4 > 50)

• Delay 8-12 weeks

• TB meningitis

• Delay 8-12 weeks

• Cryptococcal

meningitis

• Delay 2-10 weeks

Summary Incidence of IRIS ~10-15%.

Know the risk factors for IRIS (CD4 < 100)

Presentation varies depending on the OI

Start HAART within 2 weeks of initiation of OI treatment.

◦ TB – start within 2 weeks if CD4 <50, otherwise delay 8-12 weeks

◦ TB meningitis – delay 8-12 weeks regardless of CD4

◦ Cryptococcal meningitis – delay 2-10 weeks

Management of IRIS

◦ NSAIDs and steroids

◦ Continue HAART

Prevention: initiate HAART before the development of advanced AIDS

Questions?